Gastroesophageal reflux (GER) is frequent in children with asthma, can induce bronchospasm, and increase airways reactivity. Children with asthma are often treated for GER with drugs to suppress gastric acid production. However, this treatment is expensive, and with unproven benefit. The primary objective in this proposal is to conduct a multi-site, randomized, clinical trial to test the hypothesis that treatment of GER with lansoprazole, an approved proton pump inhibitor, will decrease the frequency of exacerbations in children with poorly controlled asthma. The study will include 300 asthmatic children treated with inhaled corticosteroids, 6-16 years of age, with poor control defined by frequent symptoms, excessive beta agonist use, or frequent exacerbations. Participants will be randomly assigned to treatment with either lansoprazole or placebo for six months. The presence, severity, and relationship of GER to asthma symptoms will be determined with 24 hour esophageal pH monitoring, but randomization to treatment will not be influenced by the presences or severity of GER. The primary outcome measure is the proportion of participants who have exacerbations of asthma defined by diaries and interviews. Secondary outcome measures include asthma symptom and control scores, GER symptoms, lung function, and unscheduled health care contacts. Pre-defined subgroup analyses will examine the relationship between specific clinical features and the response to lansoprazole. Treatment response will also be evaluated with 3-hour post-dose plasma lansoprazole concentrations, and related to polymorphisms in CYP2C19, the cytochrome P450 pathway, and IL-1 beta, a pro-inflammatory cytokine. Tertiary studies will determine how the magnitude of GER impacts airways inflammation, as measured by the concentrations of H+ (pH) and NO in expired breath. The results of this trial should have a major impact on the understanding and treatment of GER in children with asthma.